Alkoxy-caffein and process of making same.



UNITED STATES Patented April 12, 1904.

PATENT OFFICE.

-MITFORD C. MASSIE, OF WASHINGTON, DISTRICT OF COLUMBIA, ADMIN- ISTRATOR OF FRITZ ACH, DECEASED, ASSIGNOR TO C. F. BOEHRINGER & SOEHNE, OF MANNHEIM-WALDHOF, GERMANY, A FIRM.

ALKOXY-CAFFEIN AND PROCESS OF MAKING SAME.

SPECIFICATION forming part of Letters Patent No. 757,330, dated April 12,1904. Original application filed April 16, 1898, Serial No. 677,857. Divided and this application filed February 10, 1903. Serial No. 142,777. ($pecimens.)

To all whom it may concern:

Be it known that FRITZ AoH, deceased, late a citizen of Germany, and a resident of Mannheim, Germany, did invent new and useful Improvements in AlkoXy-Calfeins and Method of Preparing Same; and I, MITFORD C. MASSIE, the duly-constituted administrator of the estate of said FRITZ AOH, deceased, do hereby declare the following to be a full, clear, and exact description of the said invention of said decedent, such as will enable others skilled in the art to which it appertains to make and use the same.

The present invention relates to the art of preparing caifein derivatives, and in particu- August 26, 1902, of which the present application is a division, there are described and claimed one class of the said c0mpoundsviz. 3alkoXy-8-chloro-calfeinand the method of preparing the same. As stated in said patent, the inventor discovered that in these substituted chloro-caffeins the chlorin atom attached to the carbon atom in the position 8 may, just as in chloro-caflein proper, be replaced by hydrogen,methoxyl,ethyl,hydroxyl,orthe amido group. We are thus enabled to-obtain series of new uric-acid and xanthin derivatives. Thus, for example, if we cause an alkali-methylate, such as sodium-methylate, to act upon 3methyoxy-S-chloro-caifein, obtained by the action of methyl alcohol upon 38dichloro caffein, the new compound 38-dimethoXy-caffein is produced according to the equation:

OHaN- CO I CH3 cH,.o.cH2.N-c- I (3-methoxy-B-chloro-caifein) can-co I I OH 00 C-N +NaCl (3-8-dimethoxy-caffein) lar those new derivatives having the gro O.CH2 1 C 11, 011nd to the nltrogen ato By proceeding indirectly by way of this methoxy compound the chlorin atom (8) is in this case replaced by hydroxyl, just as in the case of chloro-caflein itself. Thus if 38- dimethoxy-cafiein is cautiously heated with. dilute hydrochloric acid the methoxyl group bound to the carbon atom (8) is split off as methyl-chlorid, 3methoxyhydroxy caflein being formed according to the equation:

CHalTT-(FO OC CN l n oo1 CH3.O.CH2.NC-N

(3 metl10xy-8-chlorocaffein) CHaN-CO I 1 oc CN CH3+CH3.CI

. (3'-methoxy-caffein) The latter process of preparing the 3- met hoxy-caifein and the product itself are not herein claimed, since they form the subject-matter covered in Patent No. 667 ,380, dated February 5, 1901. They are simply referred to by way of illustration. The present invention consists in the methods of treatment of the 3-alkoXy-8-chlor0- caifein for the purpose of replacing the chlorin atom in the position 8 by hydrogen or its Ioo radicals above mentioned and in such other features, steps, and combinations of steps as will hereinafter be set forth.

The invention will now be illustrated by the following detailed description of processes and the resultant compounds, which constitute what are considered the preferred embodiment of the said invention.

1. Preparation 0 f 3-8-cZimet/wwy-crqfen. For the purpose of a full disclosure the starting material 3-methoXy8-chlorocaifein and the method of preparing the same will be first described. For this purpose 3methoxycaf V fein, a compound which, together with its method of production, is described and claimed in Patent No. 667,380, dated February 5, 1901, granted to C. F. Boehringer & Soehne, as assignees of this inventor, will be used as the starting material. In preparing the 3f,- methoxy-8-dichlorocaffein in its pure and crystalline condition it is not necessary to start with the 3-8-dichlorocaiiein; but one may employ directly the syrup or resinous substance which according to the above patent serves for the production of the crystalline product 3-8-dichloro-cafi'ein. Such syrup is boiled, together with about twenty times its weight of absolute methyl alcohol, for from five to six hours in a reflux cooler. The alcohol is then distilled off completely, and the residue is taken up with ether and washed with water to remove the hydrochloric acid. The ether is evaporated and a little (about two parts) methyl alcohol is poured over the residue, which after some time begins to solidify to a crystalline mass. This crystalline mass is then redissolved in 'methyl alcohol and recrystallized therefrom, whereby the new body 3-methoxy-S-chloro-caffein is obtained in the form of fine shining needles felted together asbestos-like. corresponding to the formula CaHnNrOgCl, the constitution of the new compound being represented in the structural formula OH3.NOO

| CH3 OC C-N l col *CHaQCHaN-O-N This new compound 3-methoXy-8-chloro-caf fein melts at 129 to 130 centigrade. With dilute nitric acid or with chlorin water" it gives a strong murexid reaction. It is readily soluble in boiling water, hot alcohol, benzol, acetone, acetic ether, and'chloroform. It is, moreover, readily soluble in fuming hydrochloric acid. If this solution is heated for some time on the water-bath, however, decomposition takes place, chloro-paraxanthin, which separates in the form of coarse colorless prisms, being formed, attended by a splitting off of formic-aldehyde and methyl-chlorid.

For the manufacture of the 3-8dimethoxy An analysis of them gives figures caffein one part, by weight, of 3-methoxy8 chloro-caifein is dissolved in ten parts, by weight, of methyl alcohol and heated to the boiling-point for about half an hour, together with somewhat more than the necessary quantity, according to computation of sodiummethylate. The mass is then evaporated to drive off the alcohol and the crystalline residue taken up with water. The resultant product after being recrystallized from dilute alcohol is then obtained in the form of fine needles aggregated concentrically, whose analysis shows them to have the formula CwHaNiOi. This new compound 38-dimethoxy-caifein has the structural formula OIIaN-GO I I CH3 OC CN.

I u oocH3 CH3. 0. CH2. N- (J N It melts at 153 centigrade and gives a strong murexid reaction with dilute nitric acid or with chlorin water. It is readily soluble in hot water, methyl alcohol, and ethyl alcohol and benzol, and in cold acetone, chloroform, and acetic ether. In alkalies it is insoluble, but readily soluble in concentrated hydrochloric acid, by which, however, it is rapidly decomposed.

2. Preparation of 3-meth0wy-8hydr0mycafein.1n this process 3'-8-dimethoXycaffein just described serves as a starting material, one part of the same, by weight, in a finely-powdered condition, being cautiously heated on the water-bath, together with about ten parts of hydrochloric acid of ten per cent. strength, the heating being continued until solution has taken place. During this treatment a copious evolution of methyl chlorid occurs. The solution being completed, the same is cooled with ice-water, whereby fine colorless acicular crystals are thrown out.

After standing for. several hours (four to five) the liquor is drained from the crystals by tiltration, and they are washed with ice-water. The resultant product is recrystallized from methyl alcohol, whereby coarse colorless needles are obtained whose formula, according to analysis, is G9H11N404- This 3-methoXy-hydroXy-caffein has the structural formula IOC IOC

IIC

IIE

' thereto gives rise to a silver salt of the same,

after boiling off the ammonia said silver salt crystallizing in the form of fine needles. 3- methoXy-hydroxy-cattein gives a strong murexid reaction.

What is claimed, and desired to be secured by Letters Patent of the United States, is-

1. The process of preparing 3'-8-dialkoxycafiein, which consists in treating 3-alkoxy- 8-chloro-caflein with alkali-alkylate.

2. The process of preparing 3-8-dimethoxy-cafiein, which consists in treating 3- inethoxy-S-chloro-cafiein with sodium-methyate.

3. The process which consists in preparing 3-8-dimethyl-caflein, which consists in dis' solving 3-methoxy-S-chloro-calfein in methyl alcohol and heating the solution to the boilingpoint together with sodium-methylate, in the proportions, substantially as stated.

4. The process of preparing 38-dimethyl caffein which consists in dissolving 3methoxy S-chIorO-caffein in methyl alcohol and heating the solution to the boil ing-point, together with sodium-methylate, in the proportions substantially as stated, then evaporating and taking up the residue with water. I

5. The process of preparing 3-alkoXy8-hy'- droXy-catfein, which consists in treating di. alkoxy-calfein with hydrochloric acid.

6. The process of preparing 3 -methoXy-8- hydroxy-catfein, which consists in heating 3- S-dimethoxy-cafiein with hydrochloric acid.

7. The process which consists in heating 3'- S-dimethoxy caffein on the water bath, together withdilute hydrochloric acid until solution takes place, all in the proportions, substantially as specified.

8. The process of preparing 3-methoxy8- hydroxy-cafiein, which consists in heating 3'- S-dimethoxy caflein on the water bath, together with dilute hydrochloric acid until solution takes place, all in the proportions substantially as specified, then cooling, then allowing to stand, and then draining the resultant crystals.

9. The process of preparing 3-methoXy-8 hydroXy-caffein, which consists in heating 3- dimethoXy-cafiein on the water-bath, together with dilute hydrochloric acid until solution takes place, all in the proportions substantially as specified, then cooling, then allowing to stand, then draining the resultant crystals, and, finally, after washing the crystals with ice-Water, recrystallizing from methyl alcohol.

10. The process which consists in acting upon 38-dichloric calfein with an alcohol and treating the resultant 3-alkoXy-8-chloro caflein with an alkali-methylate.

11. The process which consists in acting upon 38dichloro'cafl ein with methyl-alcohol and then treating the resultant 3-methoxy8- chloro-cafiein with sodium-methylate.

12. The process which consists in acting upon 38-dichloro-cafi:'ein with an alcohol, then treating the resultant 3alkoXy8-chlorocaflein with alkali-methylate and, finally, treating the resultant dialkoxy-cafiein with H l.

13. The process which consists in acting upon 3'8-dichlorocafl"ein with methyl-alcohol, then treating the resultant 3-methoXy-8 chloro caflein with sodium methylate, and, finally, acting upon the resultant 38dimethoXy-caflein with hydrochloric acid.

14. As a new chemical compound, 3'meth oxy-8-hydroxy-calfein having the structural formula hereinbefore given, which crystallizes in coarse colorless needles having a melting-point of about 228 to 229 centigrade,

which is readily soluble in water, hot methyl alcohol and hot ethyl alcohol, and is also soluble in alkalies, including ammonia, and which gives a murexid reaction.

In testimony whereof I aflix my signature in presence of two'witnesses.

MITFORD C. MASSIE, Acbnim'strator of the estate of Fritz Ach,

deceased. Witnesses:

ANTON GLOETZNER, ALBANUs S. T. JoHNsoN. 

